Periodontitis is a polymicrobial disease caused by the coordinated action of a complex microbial community, which results in inflammation of tissues that support the teeth. It is one of the most prevalent disabling health conditions, affecting 743 million people worldwide. The total estimated direct expenditures to treat and prevent periodontitis in the US is nearly $14.3 billion. The goal of this research program is to understand the molecular mechanisms of microbial pathogenesis and the host response to the microbial challenge associated with periodontitis progression. Dual metatranscriptomic (hostmicrobiome) analysis provides the information required to understand the activity and relative importance of the constituents in the pathogenic biofilm and host response during periodontal infection. To this end we propose the following Specific Aims: Aim 1. Identify the molecular mechanisms that are associated with the initial stages of adult chronic periodontitis progression by dual-transcriptome analysis of microbiome-host response expression profiles. Aim 2. Determine the effects of periodontal therapy (Scaling and Root Planing) on homeostasis of the subgingival environment. As a part of grant DE021553, we have successfully applied metatranscriptomic techniques to the study of periodontitis progression. Thanks to a previous collaborative effort (grant DE021127) we already have all the samples needed to complete the present proposal. The target subject population will consist of 15 chronic periodontitis individuals. The microbial changes observed will be relevant to a large proportion of subjects with periodontal disease. The patients were followed bimonthly for a period of 12 months, during which they will undergo clinical monitoring to determine which samples will be used for compassion of progressing and non- progressing sites by metagenomic and metatranscriptomic analysis. Identification of critical genes that are required for pathogenesis and information about their differential expression can be used to develop novel targeted approaches to early-stage diagnosis, treatment, monitoring and prevention. Moreover, the potential impact extends beyond the study of periodontitis because the same principles and methods potentially can be applied to other polymicrobial diseases. We believe that the team we have assembled for this project has all the qualifications to accomplish successfully the goals proposed in the present application.